<i>Mycobacterium tuberculosis</i>enoyl-acyl carrier protein reductase inhibitors as potential antituberculotics: development in the past decade

Holas, Ondřej; Ondrejcek, Pavel; Doležal, Martin

doi:10.3109/14756366.2014.959512

Cited by 34 publications

(19 citation statements)

References 44 publications

(58 reference statements)

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“…And finally, we zeroed upon the piperidine moiety. Isoniazid (INH) ( 1.1 ) is a well‐known antitubercular drug with pyridine scaffold and besides this, many six‐membered nitrogen heterocycles have been reported as a promising lead against Mycobacterium tuberculosis , especially as EACP reductase inhibitor . It has been found that 1,4‐di‐substituted piperidine derivative compound 1.2 (Figure ) has more potent antitubercular activity than the 1‐substituted piperidine derivative compound 1.3 (Figure ).…”

Section: Introductionmentioning

confidence: 99%

Targeting HIV‐TB coinfection by developing novel piperidin‐4‐substituted imines: Design, synthesis, in vitro and in silico studies

Kumar¹,

Rajappan²,

Sriram

et al. 2019

Archiv der Pharmazie

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Tuberculosis is the "Achilles heel" of the human immunodeficiency (HIV) ministration.HIV-positive people are 16-27 times more prone to contract tuberculosis. But the adverse interaction between antiretroviral drugs and antitubercular drugs has made it necessary to look for a single drug regimen for HIV-TB coinfection. Piperidine derivatives have been reported as anti-HIV and anti-TB agents. This inspired us to design, synthesize, and characterize a series of 3,5-bis(furan-2-ylmethylidene)piperidin-4-substituted imines (R1-R25) and these were further screened for in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv and anti-HIV activity. Molecular docking studies showed energetically favorable binding interactions with both EACP reductase (1ZID.pdb) and reverse-transcriptase (1REV.pdb) targets. The compounds R7, R12, R17, R18, R19, R20 were found to be more potent as anti-TB agents than ethambutol (MIC 3.125 μg/ml). Compound R7 was found to be moderately active with an IC 50 of 2.1 ± 0.04 μM in multicycle infection assays, in comparison with the standard drug, zidovudine (IC 50 = 5.7 ± 0.04 nM), used as anti-HIV drug. The cytotoxicity assay was done on Vero, MT-2, and TZM-bl cells to assess the safety of these compounds and they were found to be safe. From the above results, R7 seems to be a promising lead for anti-HIV and anti-TB activity.

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Section: Introductionmentioning

confidence: 99%

Targeting HIV‐TB coinfection by developing novel piperidin‐4‐substituted imines: Design, synthesis, in vitro and in silico studies

Kumar¹,

Rajappan²,

Sriram

et al. 2019

Archiv der Pharmazie

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“…Mycobacterium tuberculosis enoyl acyl carrier protein reductase ( Mt InhA) is one of the most attractive enzymes to design and develop novel drugs for tuberculosis therapy and might be a promising target for novel inhibitors active against MDR and XDR MTB . Several benzoxazoles have been studied in respect to the Mt InhA inhibition .…”

Section: Potential Targets Of Benzoxazole‐based Compoundsmentioning

confidence: 99%

Benzoxazole Derivatives as Promising Antitubercular Agents

Šlachtová

Brulíková

2018

ChemistrySelect

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Tuberculosis (TB) is an infectious disease caused predominantly by bacillus Mycobacterium tuberculosis (MTB). The increasing prevalence of multidrug‐resistant MTB necessitates the discovery and development of alternative drugs against tuberculosis with a new mechanism of action. Over the past years, several benzoxazole derivatives have been synthesized and screened for their biological activity. Interestingly, some of them had promising antitubercular activity. Despite that, none of the benzoxazole derivatives has entered the phase of the preclinical hit‐to‐lead optimization step in anti‐TB research. In this review, we are summarizing recently published articles that evaluate the potency of benzoxazole heterocycle in the development of novel anti‐TB agents and outlined the future aspects of this promising heterocycle.

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“…InhA is the target of isoniazid (INH) and structural analogues such as ethionamide (ETH) activated by the catalase-peroxidase KatG ( Dessen et al., 1995 ). Novel InhA inhibitors (indicated in Table 1 ), unlike INH and ETH, do not require prior activation and have potential for treatment of DR-TB while some are also bactericidal against non-replicating Mtb ( Holas et al., 2015 ; Martínez-Hoyos et al., 2016 ; Flint et al., 2020 ). KasA and KasB are targets of cerulenin, plastensimycin, thiolactomycin, and indazole sulfonamides ( Abrahams et al., 2016 ; Abrahams and Besra, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Cell Surface Biosynthesis and Remodeling Pathways in Mycobacteria Reveal New Drug Targets

Shaku

Ealand

Kana

2020

Front. Cell. Infect. Microbiol.

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Mycobacterium tuberculosis ( Mtb ), the causative agent of tuberculosis (TB), remains the leading cause of death from an infectious bacterium and is responsible for 1.8 million deaths annually. The emergence of drug resistance, together with the need for a shorter more effective regimen, has prompted the drive to identify novel therapeutics with the bacterial cell surface emerging as a tractable area for drug development. Mtb assembles a unique, waxy, and complex cell envelope comprised of the mycolyl-arabinogalactan-peptidoglycan complex and an outer capsule like layer, which are collectively essential for growth and pathogenicity while serving as an inherent barrier against antibiotics. A detailed understanding of the biosynthetic pathways required to assemble the polymers that comprise the cell surface will enable the identification of novel drug targets as these structures provide a diversity of biochemical reactions that can be targeted. Herein, we provide an overview of recently described mycobacterial cell wall targeting compounds, novel drug combinations and their modes of action. We anticipate that this summary will enable prioritization of the best pathways to target and triage of the most promising molecules to progress for clinical assessment.

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Mycobacterium tuberculosisenoyl-acyl carrier protein reductase inhibitors as potential antituberculotics: development in the past decade

Cited by 34 publications

References 44 publications

Targeting HIV‐TB coinfection by developing novel piperidin‐4‐substituted imines: Design, synthesis, in vitro and in silico studies

Targeting HIV‐TB coinfection by developing novel piperidin‐4‐substituted imines: Design, synthesis, in vitro and in silico studies

Benzoxazole Derivatives as Promising Antitubercular Agents

Cell Surface Biosynthesis and Remodeling Pathways in Mycobacteria Reveal New Drug Targets

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